Mark Bretscher

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Mark S. Bretscher
Born(1940-01-08)8 January 1940
Cambridge

Mark Steven Bretscher (born 8 January 1940) is a British biological scientist and Fellow of the Royal Society. He worked at the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom and is currently retired.

Contents

Education

Mark Bretscher was born in Cambridge and educated at Abingdon School from 1950 to 1958. [1] He then went to Gonville and Caius College, University of Cambridge in 1958 to study Chemistry where he gained a PhD and became a Research Fellow. [2]

Career

In 1961 he joined the MRC Unit for the Study of the Molecular Structure of Biological Systems in the Cavendish laboratory as a graduate student with Francis Crick and Sydney Brenner and then spent a year as a Jane Coffin Childs Fellow with Paul Berg at Stanford (1964-5). He joined the staff of the MRC Laboratory of Molecular Biology in Cambridge, becoming Head of the Division of Cell Biology (1986-1995) and Emeritus scientist (2005-2013). [2] He was a visiting professor in biochemistry and molecular biology at Harvard University (1974–75) and Eleanor Roosevelt Cancer Society Fellow and visiting professor, Stanford University (1984–85). He was elected a Fellow of the Royal Society in 1985.

Bretscher's main contributions lie in the areas of the mechanism of protein biosynthesis, the structure of cell membranes (especially that of the human red blood cell) and animal cell migration.

Protein Synthesis

In his first paper, on the genetic code, the word "codon" first appeared in print (inserted by Francis Crick). [3] Bretscher later showed that the growing polypeptide chain is attached to one of the hydroxyl groups of the terminal adenosine residue of tRNA. [4] With Kjeld Marcker he found that the initiator methionine tRNA binds directly to the peptide (P) site on the ribosome [5] and that protein synthesis can start on a circular messenger, showing that during initiation a ribosome does not need an end: the correct initiator AUG is not found by starting at one end of the mRNA and then selecting the first AUG. [6] He proposed that, during translocation, the two ribosomal subunits move with respect to each other, resulting in a hybrid site P/A site; this suggested that the movement of the peptidyl-tRNA and bound mRNA from the A site to the P site occurs in two steps. [7]

Cell membranes

Using a novel labelling agent, he showed that human erythrocytes have just two major proteins exposed on their outer surfaces (now known as the anion channel and glycophorin) and that both span the lipid bilayer with a unique orientation, the first proteins shown to span the membrane. He also discovered that the amino phospholipids, phosphatidylethanolamine and phosphatidylserine, are inaccessible from outside the cell and proposed therefore that the bilayer is asymmetrical — with choline lipids forming the outer monolayer and the amino lipids the cytoplasmic monolayer. He suggested that this asymmetry arises during membrane biosynthesis, proposing that all these lipids are made on the cytoplasmic face of the bilayer, but choline lipids are subsequently moved by a hypothetical lipid translocase to the outer monolayer which he named a "flippase". [8]

With Munro, he proposed that the Golgi apparatus concentrates cholesterol away from the cis-side of the Golgi towards the trans-side. This helps keep the level of cholesterol at a high level in the plasma membrane, making it a better barrier for the cell. The presence of cholesterol makes a bilayer thicker: the increasing thickness of the membrane from cis- to trans- leads to a filtration of only those proteins having a long enough transmembrane domain to advance to the cell surface. This is a novel form of protein sorting. [9]

Cell Movement

He is the principal protagonist of the membrane flow scheme for cell locomotion, which is largely based on how cap formation occurs [10] and the movement of carbon particles on the surfaces of migrating fibroblasts studied by Michael Abercrombie. [11] Abercrombie suggested his particle movement reflected motion of the surface from the cell's front to its rear, and that the front was extended by addition of membrane there from internal stores. Most mammalian cells continuously circulate their surface membrane in a process driven by the endocytic cycle. Clathrin [12] coated pits in the plasma membrane bud a segment of the surface into the cell; this membrane is processed through various intracellular compartments and then returned to the cell surface. [13] When cells move — a process called amoeboid movement — the cell's front is extended ahead of the cell and the rear end of the cell is then brought forward. Bretscher extended Abercrombie's view that the cell's leading edge is extended by the addition of intracellular membrane to it by exocytosis and this membrane is retrieved, by endocytosis, from regions of the cell surface nearer the cell's rear. This circulating membrane is restricted to a few proteins (mainly receptors which bring nutrients, such as LDL or transferrin) into the cell and lipids. In this way, a polarised endocytic cycle is set up, one leg of it being in the cell's surface, the other its transit through the cell: this spatial separation in the cell's surface between the sites of exocytosis (the front) and the sites of endocytosis (further back) causes a flow of membrane from the cell's front towards its rear. For many purposes, this flow can be thought of as a "lipid flow": it causes large aggregates on the cell surface, such as attached carbon particles, cross-linked surface proteins or cross-linked lipids [14] to be swept towards the back of the cell. [15] However, surface proteins which have not been cross-linked would also tend to be swept backwards, but their distribution on the cell surface is approximately randomized by Brownian motion. [16] He showed that addition of recycling membrane on moving cells occurs at the cell's leading edge. [17] He suggested that the role of the cytoskeleton in this process is to transport intracellular membrane to the front of the cell and to help structure the newly exocytosed membrane at the cell's front. In this view, the cell is somewhat like a tank, the surface attached to the substrate acting as a tread to move the cell forward. The feet of the cell (usually integrins) also circulate to provide fresh attachments for the cell's front. [18]

The rate of membrane circulation about matches that needed to move the cell forwards; studies with Dictyostelium discoideum amoebae show that, in this fast moving (about 15μm/min) cell, they internalise their entire surface once about each 6 mins. [19] Furthermore, ts mutants in NSF, a protein required for membrane fusion, stop moving at the restrictive temperature. [20] Strikingly, both Dictyostelium amoebae and neutrophils can chemotax towards a target whilst in suspension, showing that a solid substrate is not required for movement; this provides strong evidence that these cells move by a flowing membrane. [21] [22]

Family

His father was Egon Bretscher, the nuclear physicist. [23] He is married to Barbara Pearse and his brothers are Anthony Bretscher and Peter Bretscher. He lists his hobbies as "walking, creating wild environments, early English portraits and furniture."

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<span class="mw-page-title-main">Lipid bilayer</span> Membrane of two layers of lipid molecules

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References

  1. ↑ "Valete et Salvete" (PDF). The Abingdonian.
  2. 1 2 "Mark S. Bretscher". MRC Laboratory of Molecular Biology.{{cite web}}: CS1 maint: url-status (link)
  3. ↑ Bretscher, MS; Grunberg-Manago, M (1962). "Polyribonucleotide-directed protein synthesis using an E. coli cell-free system". Nature. 195 (4838): 283–284. Bibcode:1962Natur.195..283B. doi:10.1038/195283a0. PMID   13872932. S2CID   4292916.
  4. ↑ Bretscher, MS (1963). "The Chemical Nature of the s-RNA-polypeptide Complex". J Mol Biol. 7 (4): 446–449. doi:10.1016/s0022-2836(63)80037-6. PMID   14066620.
  5. ↑ Bretscher, MS; Marcker, KA (1966). "Polypeptidyl-s-ribonucleic acid and amino-acyl-s-ribonucleic acid binding sites on ribosomes". Nature. 211 (5047): 380–384. doi:10.1038/211380a0. PMID   5338626. S2CID   4208941.
  6. ↑ Bretscher, MS (1968). "Direct translation of a circular messenger DNA". Nature. 220 (5172): 1088–1091. Bibcode:1968Natur.220.1088B. doi:10.1038/2201088a0. PMID   5723604. S2CID   4240408.
  7. ↑ Bretscher, MS (1968). "Translocation in protein synthesis: a hybrid structure model". Nature. 218 (5142): 675–677. Bibcode:1968Natur.218..675B. doi:10.1038/218675a0. PMID   5655957. S2CID   4191051.
  8. ↑ Bretscher, MS (1973). "Membrane structure: some general principles". Science. 181 (5126): 622–629. Bibcode:1993Sci...261.1280B. doi:10.1126/science.8362242. PMID   8362242.
  9. ↑ Bretscher, MS; Munro, S (1993). "Cholesterol and the Golgi apparatus". Science. 261 (5126): 1280–1281. Bibcode:1993Sci...261.1280B. doi:10.1126/science.8362242. PMID   8362242.
  10. ↑ Taylor, RB; Duffus, WP; Raff, MC; de Petris, S (1971). "Redistribution and pinocytosis of lymphocyte surface immunoglobulin molecules induced by an anti-immunoglobulin antibody". Nature New Biology. 233 (42): 225–229. doi:10.1038/newbio233225a0. PMID   20480991.
  11. ↑ Abercrombie, M; Heaysman, JE; Pegrum, SM (1970). "The locomotion of fibroblasts in culture. I. Movements of the leading edge". Exp Cell Res. 59 (3): 393–398. doi:10.1016/0014-4827(70)90646-4. PMID   4907703.
  12. ↑ Pearse, BM (1987). "Clathrin and coated vesicles". EMBO J. 6 (9): 2507–2512. doi:10.1002/j.1460-2075.1987.tb02536.x. PMC   553666 . PMID   2890519.
  13. ↑ Anderson, RG; Brown, MS; Goldstein, JL (1977). "Role of the coated endocytic vesicle in the uptake of receptor-bound low density lipoprotein in human fibroblasts". Cell. 10 (3): 351–364. doi:10.1016/0092-8674(77)90022-8. PMID   191195. S2CID   25657719.
  14. ↑ Stern, PL; Bretscher, MS (1979). "Capping of exogenous Forssman glycolipid on cells". J Cell Biol. 82 (3): 829–833. doi:10.1083/jcb.82.3.829. PMC   2110488 . PMID   389939.
  15. ↑ Bretscher, MS (1984). "Endocytosis: relation to capping and cell locomotion". Science. 224 (4650): 681–686. Bibcode:1984Sci...224..681B. doi:10.1126/science.6719108. PMID   6719108.
  16. ↑ Bretscher, MS (1976). "Directed lipid flow in cell membranes". Nature. 260 (5546): 21–23. Bibcode:1976Natur.260...21B. doi:10.1038/260021a0. PMID   1264188. S2CID   4291806.
  17. ↑ Bretscher, MS (1983). "Distribution of receptors for transferrin and low density lipoprotein on the surface of giant HeLa cells". Proc Natl Acad Sci U S A. 80 (2): 454–458. Bibcode:1983PNAS...80..454B. doi: 10.1073/pnas.80.2.454 . PMC   393396 . PMID   6300844.
  18. ↑ Bretscher, MS (1996). "Getting membrane flow and the cytoskeleton to cooperate in moving cells". Cell. 87 (4): 601–606. doi: 10.1016/s0092-8674(00)81380-x . PMID   8929529. S2CID   14776455.
  19. ↑ Aguado-Velasco, C; Bretscher, MS (1999). "Circulation of the plasma membrane in Dictyostelium". Mol Biol Cell. 10 (12): 4419–4427. doi:10.1091/mbc.10.12.4419. PMC   25767 . PMID   10588667.
  20. ↑ Thompson, CR; Bretscher, MS (2002). "Cell polarity and locomotion, as well as endocytosis, depend on NSF". Development. 129 (18): 4185–4192. doi:10.1242/dev.129.18.4185. PMID   12183371.
  21. ↑ Barry, NP; Bretscher, MS (2010). "Dictyostelium amoebae and neutrophils can swim". Proc Natl Acad Sci U S A. 107 (25): 11376–11380. Bibcode:2010PNAS..10711376B. doi: 10.1073/pnas.1006327107 . PMC   2895083 . PMID   20534502.
  22. ↑ Bretscher, MS (2014). "Asymmetry of single cells and where that leads". Annu Rev Biochem. 83: 275–289. doi:10.1146/annurev-biochem-060713-035813. PMID   24437662.
  23. ↑ "Egon Bretscher profile". Atomic Heritage Foundation.

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